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Abstract

Background

Deep brain stimulation of the subthalamic nucleus significantly improves motor function
in patients with severe Parkinson's disease. However, the effects on nonmotor aspects
remain uncertain. The present study investigated the effects of subthalamic nucleus
deep brain stimulation on mood and psychosocial functions in 33 patients with advanced
Parkinson's disease in a three year follow-up.

Methods

Self-rating questionnaires were administered to 33 patients prior to surgery as well
as three, six, twelve and 36 months after surgery.

Results

In the long run, motor function significantly improved after surgery. Mood and psychosocial
functions transiently improved at one year but returned to baseline at 36 months after
surgery. In addition, we performed cluster and discriminant function analyses and
revealed four distinct psychosocial profiles, which remained relatively stable in
the course of time. Two profiles featured impaired psychosocial functioning while
the other two of them were characterized by greater psychosocial stability.

Conclusion

Compared to baseline no worsening in mood and psychosocial functions was found three
years after electrode implantation. Moreover, patients can be assigned to four distinct
psychosocial profiles that are relatively stable in the time course. Since these subtypes
already exist preoperatively the extent of psychosocial support can be anticipatory
adjusted to the patients' needs in order to enhance coping strategies and compliance.
This would allow early detection and even prevention of potential psychiatric adverse
events after surgery. Given adequate psychosocial support, these findings imply that
patients with mild psychiatric disturbances should not be excluded from surgery.

Background

Parkinson's disease (PD) is a progressive movement disorder ensuing from dopaminergic
depletion of the basal ganglia, substantia nigra pars compacta. The resulting disruption
of the motor circuit that connects the basal ganglia to the motor cortex leads to
the clinical manifestations of tremor, rigidity, bradykinesia and postural instability.
Since limbic and associative loops are also affected by dopaminergic loss, cognitive
and behavioural abnormalities are frequently encountered in PD patients [1-4].

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment
to improve motor function in patients with advanced Parkinson's disease. Studies with
respect to short- and long-term efficacy of STN-DBS have shown marked improvements
in motor function as well as a reduction of antiparkinsonian drug treatment [5-7].

However, the effects of STN DBS on psychosocial functions are not well understood.
Some studies reported positive changes in mood, depression and anxiety after surgery
[8-10].

Several investigations showed adverse effects of STN DBS on mood. Although many of
them were single case reports, documented mood changes include depression [11-13](hypo)mania [14-17],visual hallucinations [18] and behavioural changes, like apathy, irritability, emotional lability, hypersexuality and aggressiveness [5,12,17,19]. Some behavioural abnormalities were related to electrode displacement [15,20,21] or to stimulation parameters [18,22-24]. Changes may also be related to activity modification within the basal ganglia-thalamo-cortical
circuits by chronic stimulation of the STN.

Since there are hardly any long-term studies, the effects of STN DBS on mood are incompletely
understood. The aim of the current study was to investigate both short- and long-term
effects of STN-DBS on mood and psychosocial functions in a consecutive series of 33
patients with idiopathic PD. We analyzed patient data of the short-term follow-up
that have been gathered in the study of Kalteis et al (2006) and additionally collected
long-term data of the same patients [25].

Methods

Patients

Patients were selected for STN DBS according to the CAPSIT-PD protocol [26]. Subjects had to meet following inclusion criteria: diagnosis of idiopathic PD determined
by the presence of at least two of the four cardinal motor symptoms; intractable motor
fluctuations, disabling dyskinesias or freezing episodes; clear responsiveness to
dopaminergic substitution therapy, demonstrated by an apomorphine test before surgery
[27]; inconspicuous brain magnetic resonance imaging (MRI) scan. Exclusion criteria were
previous neurosurgical history, native language other than German, substance abuse,
a mini-mental state examination score (MMSE) below 24, presence of a severe psychiatric
disease based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)
and withheld informed consent.

35 consecutive patients obtained bilateral STN DBS during the assessment period. Two
subjects generally refused to participate in the study. Hence, in the present investigation
data of 33 PD patients (22 men, 11 women) were evaluated at baseline (see Table 1). One year after surgery patient number declined to 31 due to two deaths that were
unrelated to STN DBS. During the long-term follow-up two patients withdrew informed
consent, one patient died and one patient was excluded due to severe cognitive deterioration.
In summary 27 subjects completed the entire investigation.

The present study was approved by the Ethics-Committee of the Medical University of
Vienna (trial registration number: 353/96).

Surgical procedure

35 patients were treated with bilateral implantation surgery in a single operative
session (Lead 3389, Medtronic Inc.). Due to a lack of cooperation one patient received
the brain electrodes in two procedures. Implantation of pulse generators was performed
in a second procedure one week later. We used the same surgical procedure which was
described elsewhere (25).

Assessments

To investigate short- and long-term effects of STN DBS all patients administered clinical
and self-rating questionnaires prior to surgery and four times postoperatively (three,
six, twelve and 36 months). To establish a baseline score, patients were assessed
three times prior to electrode implantation, in fact eight to six weeks, four weeks
and two weeks.

Before surgery motor symptoms were evaluated on and off medication, however psychological
assessments were exclusively conducted in the on state. After surgery patients were
assessed while receiving medication with stimulators turned on.

Psychological assessment

Prior to surgery all patients underwent a comprehensive psychological evaluation.
The psychological assessment included well-established self-rating scales commonly
used in the assessment of mood, psychological symptoms and distress. All scales used
were valid and reliable as well as recommended to evaluate treatment effects.

Profile of Mood Scale (POMS)

This modified version consists of 35 adjectives clustered in four subscales (Depression,
Fatigue, Vigor, Irritability) by which subjects describe their mood during the week
before [28].

Visual Analogue Scale for Well-being (VAS)

The patient has to state his present condition on a line with two extreme poles of
well-being and discomfort [29].

Beck Depression Inventory (BDI)

The BDI is a commonly used 21-item questionnaire measuring depressive symptoms [30].

Self-Report Symptom Inventory 90 Items-Revised (SCL-90-R)

The SCL-90-R measures impairments due to somatic and psychological symptoms and distress.
It comprises nine subscales and three global judgements [32].

Sickness Impact Profile (SIP)

The SIP is a 136-item generic quality of life instrument and consists of 12 categories
that can be divided into a physical and a psychosocial domain of quality of life [33].

Unified Parkinson's Disease Rating Scale (UPDRS)

The severity of motor symptoms is assessed with the UPRDS-Scale [34]. Part II (activities of daily living) and III (motor examination) were evaluated
for the study.

Data analysis

Paired t-tests were performed and analyses of variance using assessment time as repeated
measure to compare the time points. Due to multiple time points we chose the significance
level at p ≤ 0,01.

To identify patient groups a cluster analysis was performed on the preoperative data.
The squared Euclidean distance was used as a proximity measure. The number of clusters
was determined by ending the hierarchical clustering with Ward's minimum variance
method at a sharp increase in the error sum of squares. This criterion indicates that
much of the accuracy of classification would be lost by further reducing the number
of groups. Discriminant function analysis was performed to reassess the results of
the cluster analysis. Additionally we conducted discriminant function analyses to
predict group membership one year and three years postoperatively.

Furthermore, we calculated the Kruskal-Wallis test to compare age, education, disease
duration and MMSE-score of the four subtypes. Age differences were calculated using
the Chi-Quadrate test (Pearson). Results are presented as mean (± SD), otherwise indicated.

We analyzed patient data that have been collected in the study of Kalteis et al (2006)
and additionally collected data three years postoperatively using the same test battery
[25].

Results

Analysis of the preoperative Data

Baseline data were collected at three times prior to surgery (eight to six weeks,
four weeks and two weeks). Since there were hardly any differences between the preoperative
assessments we combined the preoperative scores to one baseline mean score. The only
exception found was Anxiety. The subscale Anxiety (SCL-90-R) increased significantly from six to two weeks prior to surgery (means:
0,79 ± 0,5, 0,92 ± 0,42, T = -2,934, p = 0,007), close to the surgery date anxiety
was significantly higher. This finding is not surprising as the surgical procedure
was performed in awake patients off medication.

Group classification – cluster analysis

Cluster analysis at baseline

Data of one patient were missed for the POMS and SIP scales; therefore we performed
the analysis with 32 patients. Cluster analysis of all self rating scales at baseline
identified four patient subtypes. Subtypes 1 and 2 had low well-being and higher distress
level, subtypes 3 and 4 had better well-being and less distress compared to the other
groups. Mean scores are listed in Table 2.

Table 2. Mean scores of the four patient subtypes in the self-rating scales and tests of equality
of group means

Cluster 1 Very low well-being and moderate sickness impact

One fourth of the patients reported very low well-being (n = 8). They suffered from
clinical relevant depressive symptoms, increased state and trait anxiety, high distress,
but moderate sickness impact.

Cluster 2: Low well-being and a high sickness impact

22 percent described low well-being, moderate depressive symptoms and increased state
and trait anxiety (n = 7). Their distress level was moderate and their sickness impact
on quality of life was high.

Cluster 3: Slight decreased well-being and low sickness impact

Cluster 4: Good well-being, little sickness impact

22 percent of patients estimated their well-being as good (n = 7). Compared to other
subtypes few depressive symptoms, low anxiety, distress and sickness impact featured
this cluster.

The four subtypes did not differ in age, education and disease duration (Table 3). Regarding the cognitive screening there was a trend toward significance (p = 0,018).
Subtype 2 indicated the lowest MMSE score. To confirm the results of the cluster analysis
we additionally performed a discriminant function analysis of the baseline data. The
four cluster types again differed significantly from each other (Wilks' Lambda = 0,000,
Chi-square 161,34, p = 0,000, Table 2). The procedure generated a set of discriminant functions based on linear combinations
of the predictor variables that provided the best discrimination between the groups.
Fisher's linear discriminant functions were generated from our sample at baseline
for which group membership was defined by the cluster analysis (Table 4). Profile classification was accurately (100%) repeated in all patients which confirmed
the results of the cluster analysis to the highest extent. Based on the high accordance
of both statistical procedures the discriminance functions can be applied to new cases
to predict group membership.

Table 3. Mean scores ± SD of the four patient subtypes and total (age, education, disease duration,
MMSE, and distribution between the sexes)

Discriminant function analysis one year after surgery

On the basis of the one-year follow-up assessment discriminance analysis again revealed
significant results. Twelve months postoperatively the four profiles still significantly
diverged from each other (Wilks' lambda = 0,000, Chi-square = 131,3, p = 0,000). The
predicted classification remained completely unchanged in 30 patients (two patients
were lost due to death). Mean scores differed significantly from baseline, in fact
patients showed improvements in almost all self-rating scales one year after surgery.
Despite of this clear amelioration the four patient subgroups still differed significantly.
Group 1 (n = 7) and 2 (n = 6) exhibited an impaired psychosocial profile at baseline
compared to the other groups (cluster 3: n = 10, cluster 4: n = 7). Group 1 and 2
improved their mean scores but both groups still demonstrated an impaired profile
compared to the others.

Discriminant function analysis three years after surgery

The discriminance analysis of the three-year follow-up showed the same significant
pattern as before. Even three years after surgery the four profiles remained stable
(Wilks' lambda = 0,000, Chi-square = 114,23, p = 0,000). Noteworthy, mean values of
the clinical self-rating scales returned back to baseline level but the profile classification
still distinguished between patient groups. A total of 26 patients (one excluded because
of missing baseline data) was correctly classified to cluster 1 (n = 7), cluster 2
(n = 5), cluster 3 (n = 7) and cluster 4 (n = 7).

Pre- and postoperative changes of mood and psychosocial functions

Changes in mood and psychosocial functioning in the course of time are highlighted
in detail as follows. All means (± SD), test statistics and p-values are represented
in Table 5.

POMS

The scores of three subscales (Depression, Fatigue, Vigor) of this self-rating scale transiently declined in the time course. However, there
was just a trend towards significance (p = 0,014, p = 0,013, p = 0,016). The fourth
subscale Irritability remained unchanged between time points.

Well-Being (VAS)

The estimation of well-being differed significantly (p = 0,007) in the course of time.
The scores of well-being increased after the surgery up to six months, then slightly
decreased but still differed from baseline. At 36 months well-being declined again
and returned to baseline level.

BDI

Depressive symptoms diminished significantly after surgery and remained stable up
to one year (p < 0,001). In the three-year follow-up the extent of depressive symptoms
increased and returned to baseline level.

STAI

State and trait anxiety displayed significant changes (both: p < 0,001). The degree
of anxiety decreased after surgery and lasted up to one year. At three years after
surgery it returned to baseline level.

SCL-90-R

The extent of somatic symptoms (Somatization) declined significantly and remained stable up to one year (p < 0,001). Afterwards
it increased but still significantly differed from baseline.

Obsessive-compulsive symptoms declined after surgery (p = 0,008). This amelioration persisted up to one year. Three
years after surgery the symptoms increased and returned to baseline level.

Interpersonal Sensitivity improved after surgery up to one year. In the three-year follow-up it did not differ
significantly from baseline (p < 0,001).

This development also applied to the subscale Depression (p < 0,001).

Anxiety (p < 0,001) significantly improved three months after surgery. One year postoperatively
the score slightly augmented and further increased in the three-year follow-up but
still was significantly lower compared to baseline level (p = 0,002). Prior to surgery
Anxiety was the only variable that exhibited a marked increase due to the impending
surgery.

Psychotic symptoms declined postoperatively up to 6 months. One year after surgery they slightly worsened
but still differed from baseline (p = 0,001). Three years postoperatively psychotic
symptoms returned to baseline level again.

The subscales Hostility, Phobic Anxiety, Paranoid Ideation and Positive Symptom Distress Index exhibited no significant changes between the assessments. The Global Severity Index significantly changed in the course of time (p < 0,001). After surgery the index score
declined and remained stable up to one year, thereafter it increased and returned
to baseline level.

SIP

Significant changes were also found in the psychosocial (p < 0,001) and physical domain
(p < 0,001) in the course of time. Both scores improved immediately after surgery
at three months and persisted up to one year. Three years postoperatively the amelioration
was absent as the scores declined to baseline level.

UPDRS

STN DBS led to a significant improvement in activities of daily living (part II).
Prior to surgery patients were assessed during the off as well as during the on state.
Compared to the off state (baseline med off: 21,5 ± 6,9) there was a significant and
outlasting improvement in the on state with stimulators turned on (one year: med on/stim
on = 7,3 ± 3,8; three years: med on/stim on = 9,1 ± 5,7, both p = < 0,000). However,
there was no significant difference between the preoperative on state (med on: 12,0
± 5,9, p = 0,014) and postoperative scores.

Discussion

The present results suggest that prior to surgery patients with Parkinson's disease
can be assigned to four distinct psychosocial profiles. Even three years after STN
DBS this patient classification remained unchanged. Up to one year postoperatively
there was transient improvement in mood which had no influence on group membership.
The improvement disappeared in the three-year follow-up as scores returned back to
baseline level. In conclusion, STN DBS only transiently improved mood and psychosocial
functioning at one year. In the three-year follow-up this positive effect disappeared
and returned to baseline. Thus, in the long run there was no deterioration in mood
and psychosocial functioning compared to the preoperative state.

A cluster analysis revealed different psychosocial profiles that varied in well-being,
depressive and anxious symptoms, distress and sickness impact. Two clusters were characterized
by low well-being and moderate to high sickness impact. By comparison, the other groups
were less impaired in psychosocial functioning.

Three, six and twelve months after surgery all patients improved their psychosocial
characteristics but patients of cluster one and two still showed disadvantageous profiles.
Three years postoperatively these ameliorations were absent but the profiles of all
clusters remained relatively unchanged compared to baseline level.

Based on the patient classification of the cluster analysis it may possible to individually
adjust psychosocial support to patients' needs. We assume that patients appending
to cluster one or two might need more psychological support, patients of cluster three
and four need less. The required amount of psychological support could be determined
even prior to surgery as the psychosocial profiles remained unchanged in the course
of time.

Up to one year after surgery comparisons of group means before and after surgery showed
marked improvements in the majority of psychosocial variables. Well-being significantly
increased, depressive and anxious symptoms, sickness impact as well as the distress
level declined. These results are consistent with the findings of other groups [8,9]. Scores of three subscales (depression, fatigue and vigor) of the POMS were diminished
at three, six and twelve months but these results only showed a trend towards significance.
At the three-year follow-up they returned to baseline level. The bottom line is no
impairment in mood and psychosocial functioning evolved in the long-term follow-up.
Concordantly, no significant changes in depressive or anxiety symptoms have been reported
in other studies [35,36]. Previous studies even reported worsening of depressive symptoms in a subgroup of
patients [11,13]. In a recent review the overall finding was that in larger subgroups STN DBS rather
had an antidepressant than depressant effect [37].

So far there are only few long-term studies with respect to mood alterations after
STN DBS. One study revealed a reduction of depressive symptoms but increased apathy
and thought disorders in the three-year follow-up [8]. In agreement with our results other authors found less (although not significantly)
depressive symptoms one year after surgery [5]. Three and even five years after electrode implantation there was no difference to
baseline level.

In line with previous studies the improvement of motor function declined to small
extent but remained stable during the entire observation period [5,6,38].

In a previous study depressive symptoms were significantly improved three months after
surgery, but the extent of depressive symptoms increased at twelve months and did
not differ from baseline level [7]. Compared to baseline another group found no changes after STN DBS in depressive
symptoms (six, 24 months and five years postoperatively) [38]. Accordingly in our study beneficial effects on well-being, depressive symptoms,
state and trait anxiety, as well as on sickness impact found up to one year after
STN DBS disappeared three years postoperatively.

These results suggest that motor outcome is not related to psychosocial functioning.
One might ask why mood and well-being of patients declined to the initial point even
though motor symptoms remained improved three years after surgery. One possible explanation
of that effect stems from economic psychology. According to the prospect theory values
and preferences are not entirely stable [39]. A recently gained profit or advantage soon becomes a matter of course. Based on
that new status quo, losses are experienced more powerful even though they are smaller
than the antecedent gains. This might be equally valid for the current results. Although
ADL and motor function slightly declined in the long-term follow-up there still was
a significant improvement compared to baseline. The bottom line was a net profit which
may not have been perceived by patients as they only recognized the proportionally
small loss. However, in conclusion STN DBS had beneficial effects on motor function
and activities of daily living up to three years after surgery.

In summary, STN DBS did not induce deterioration of mood and psychosocial functions
in our patients. The results showed beneficial short-term effects on mood and psychosocial
functions after one year. In the three-year follow-up these beneficial effects were
absent and scores returned to the preoperative level. Only amelioration of somatic
symptoms and anxiety measured by the Symptom-Checklist-90-R persisted up to three
years which may be related to the overall decline of motor symptoms. In this regard
it is of note that a previous study reported of a gain of quality of life in parkinsonian
patients twelve months after electrode implantation which however was restricted to
physical aspects [40]. Mental and social quality of life did not change in the course of time. Although
they used PD specific scales their findings are in line with the current results.

Based on our data we found that patients can be assigned to distinct psychosocial
profiles prior to surgery. Since patient classification did not change in the course
of time the individual amount of psychosocial support can eventually be anticipated
before surgery in order to prevent or early detect behavioural abnormalities after
STN DBS. In this regard, further studies should determine how personality traits influence
subjective well-being.

Before surgery patients of cluster 1 displayed clinical relevant depression and patients
of cluster 2 and 3 were moderately depressed. Their depressive pathology ameliorated
up to one year and long-term results revealed at least no worsening.

Inclusion criteria of the CAPSIT-PD panel recommend surgery only for patients free
of behavioural abnormalities because mainly in single case studies deterioration has
been observed after surgery [26]. Besides, behavioural abnormalities mostly appeared to be transient and results are
too heterogeneous to define universally valid selection criteria. Following the current
inclusion criteria patients with diagnosed depression are usually meant to be excluded
from STN DBS.

Despite some methodological limitations, especially the small number of patients,
our findings show that STN DBS is an effective treatment PD patients with mild psychosocial
disturbances. Based on the results of the cluster analysis it is possible to classify
patients according to their psychosocial profile even before surgery. This allows
individual determination of the extent of the collateral psychological support that
is required before surgery and even in the long run.

Conclusion

Compared to baseline no worsening in mood and psychosocial functions was found three
years after STN DBS. Moreover, our results suggest that in PD patients with no to
mild psychosocial and psychiatric disturbances, outcome is not affected by preoperative
symptom severity. Patients with mild psychiatric problems need to receive adequate
psychosocial support before and after surgery instead of being in advance excluded
from STN DBS. Those patients need more attention and psychological and medical guidance
in order to benefit from the motor improvement. Patients' caregivers and families
need to be aware of the beneficial as well as of the possible negative effects of
STN DBS. In conclusion, our study provides valuable suggestions for individual preoperative
patient management and postoperative monitoring.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

IK: interpretation and writing, IK-E: reviewing and writing, TB: support in patient
enrollment and in reviewing, DV: support in patient enrollment and in reviewing, FA:
conception and design of manuscript and final approval of the version to be published.